High-quality medical reporting is the key to building a partnership of trust.
CENTOGENE places patients first. Our comprehensive medical reports contain extensive, expert interpretation of clinical data and include differential diagnostic approaches as well as detailed interpretation of key findings.
DNA sequencing and biomarker analyses have become valuable approaches to diagnosing rare diseases. New variants that potentially cause rare diseases are identified every year, highlighting the need for a clear, consistent and reproducible classification system.
- Detailed evaluation of patients and family history
- Detailed description of the genetic testing methods
- Clear results of identified variants following international best-practice guidelines (ACMG)1,2
- Comprehensive medical interpretation with differential diagnostic approaches if applicable
- References to publications supporting the medical and scientific results
- Recommendations for follow-up analyses for specific diseases
ACMG guidelines define five classes regarding a Mendelian variant: pathogenic, likely pathogenic, uncertain significance, likely benign and benign1,2.
For some cases, variants are reported if current medical literature and/or internal evidence supports an increased disease risk associated with the variant. Frequency of the variant, in silico predictions, conservation and published data with clinical information, segregation data or functional analyses among other types of data, must all be evaluated to classify variants according to the best available knowledge at the time of reporting. As knowledge on variant frequencies and annotations dramatically increases every year, we systematically evaluate the medical literature for reports of new disease causing variants and reevaluate past classifications in case-specific manner as an important step towards improving our understanding of disease pathogenicity.
To improve our diagnostic yield, CENTOGENE has built over our years in the diagnostic business a proprietary Bio/Databank, a mutation database that includes detailed clinical information, frequency, geographic origin and results of biochemical and other "omic" analyses, if performed.
We can classify variants according to ACMG guidelines exclusively based on the strength and depth of our Bio/Databank. At CENTOGENE, thorough, uniform and comprehensive classification of variants based on highly qualified and standardized curation workflows are hallmarks of our reporting, guaranteeing our customers receive the most accurate and up to date classification possible. We systematically reevaluate newly identifed variants. Any changes in variant classification are proactively communicated to all our previous clinical cases, a testament to our commitment to patients.
For all NGS panels, all identified variants are classified according to our standardized system. Classes 1–5 are assigned based on publicly available databases ( HGMD, LOVD, UMD, etc.) as well as our internal Bio/Databank, according to a standard protocol. We cross-check sequence results with all available databases for previously reported variants. If the variant has not been reported to date, classification relies on data about the nature and frequency of the variant, in silico predictions and all available information regarding the zygosity and segregation of the identified variant in the patient’s family.
In the final step, all identified variants along with their annotations are evaluated for potential relevance to the patient's clinical symptoms and/or suspected diagnosis.
Carriership Findings in Index Patients
To ensure that we are offering the most comprehensive medical solutions, we offer free-of-charge in our CentoGenome and CentoXome reports an optional Carriership Finding section for index patients from 1st of March 2022. In this section we report pathogenic and likely pathogenic sequence variants in known genes associated with severe and early-onset autosomal recessive and X-linked disorders regardless of their incidence.
Whole Exome Sequencing (WES) analyzes the protein-coding region of the human genome (exome; ~1%). Included are genes without any known association with human disease. We classify identified variants using the above-mentioned workflow including all available information in public databases such as Online Mendelian Inheritance in Man (OMIM) and HGMD®, gene specific databases, publications (PubMed) and genotype-phenotype databases such as our CentoMD®.
Based on standard guidelines and the diagnostic setting, only variants detected in genes that are well-defined in causing human diseases are reported. From these, all relevant variants related to the phenotype of the patient are included in the report. Pathogenicity of the variant(s) is discussed in light of the clinical information provided. Taking into account the clinical picture of the patient and family history of the disorder, further diagnostic steps are recommended. Disease-associated polymorphisms with well-established clinical significance for the individual disease phenotype(s) are also reported.
By contrast, Whole Genome Sequencing (WGS) is the most comprehensive method for analyzing the genome. Enrichment artifacts and coverage issues are not a problem. WGS enables the analysis of single-nucleotide variants (SNVs), insertion-deletion variants (INDELs), structural variants (SVs) and copy number variants (CNVs) of both the exome ( ~1% of protein coding regions) and of the remaining ~99% of non-coding sequences. The reporting procedure for WGS analysis is similar to WES.
In such cases, two pathogenic or likely pathogenic genetic variants are associated with either non-overlapping clinical presentations or contribute to a single major phenotype. In some cases, it is necessary to discuss the case (before reporting) with the ordering clinician.
If requested by the clinician, we also provide information on gene variants not associated with the patient’s disease or symptoms, but that are medically actionable (incidental or secondary findings). In such cases, we report the gene variants along with any available potential treatment information (incidental or secondary findings). We report variants in 73 selected genes according to ACMG1,2 guidelines.
- WGS is the most comprehensive method to analyze the entire genome
- WES is an analysis of the protein-coding region of the human genome only (exome; ~1%)
Miller, D.T., Lee, K., Gordon, A.S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med (2021). doi.org/10.1038/s41436-021-01171-4
Miller, D.T., Lee, K., Chung, W.K. et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med (2021). doi.org/10.1038/s41436-021-01172-3